Organo-gel formulations for therapeutic applications

ABSTRACT

A composition suitable for the local delivery of cosmetic and/or pharmaceutical agents into the skin containing at least two biocompatible organic solvents, a polar lipid, a surfactant, water, urea and a thickener wherein the organic solvents include an ester and a dihydric and/or polyhydric alcohol is provided. Also disclosed are compositions that further contain a cosmetic and/or pharmaceutical agent, along with the preparation and use thereof.

TECHNICAL FIELD

This disclosure relates to a composition useful in the local delivery ofcosmetic and/or pharmaceutical agents into the skin. This compositionallows the formulation with the agent(s) to be rapidly absorbed throughthe skin and also to have a pleasing, non-greasy, non-oily appearanceand feel.

BACKGROUND

The skin is the largest organ in the body and serves important functionsthat are necessary to life. The skin acts as a barrier to the invasionof various pathogens and toxic substances. Skin is composed of the twolayers: the epidermis is the first layer; and the dermis is the layerbelow the epidermis.

However, because it must serve as a barrier to the ingress of pathogensand toxic materials, and the egress of physiologic fluids, the skin ishighly impermeable. It must be impermeable to preserve its own integritywhile at the same time maintaining the delicate dynamic electrolytebalance of the body. The skin must serve containment function; it mustalso function as a microbial, chemical, radiation and thermal barrier.

A good deal of this impermeability of the skin results from the natureof one very thin layer created by normal developmental and physiologicalchanges in the skin. After cells are formed in the basal layer, theybegin to migrate toward the skin surface, until they are eventuallysloughed off. As they undergo this migration, they become progressivelymore dehydrated and keratinized. When they reach the surface, just priorto being discarded, they form a thin layer of dense, metabolicallyinactive cells approximately ten microns (10-15 cells) thick. This layeris called the stratum corneum or the “cornified layer”. As a result ofthe high degree of keratinization of the cells which comprise thestratum corneum, a formidable barrier is created. Therefore, penetrationvia the nonpolar route, i.e., across the membrane of these cells,remains most difficult.

Accordingly, in an effort to take advantage of this route ofadministration and overcome the obstacles the skin naturally provides,the art has turned to the use of specifically selected vehicles andcarriers into which the pharmaceutical active is incorporated so thatthe vehicle or carrier aids in, or at a minimum does not adverselyaffect, the penetration of the selected active agent. The art recognizesthat to a vast degree the rate of percutaneous delivery of apharmaceutical active can be significantly decreased by the selection ofan improper vehicle.

Because of the ease of access, dynamics of application, large surfacearea, vast exposure to the circulatory and lymphatic networks, andnon-invasive nature of the treatment, the delivery ofpharmaceutically-active agents through the skin has long been apromising concept. This is true whether the bioavailability desired issystemic or dermal, regional or local.

The advantages of this form of delivery include, but are not limited to:avoidance of the risks associated with parenteral treatment; eliminationof the inconveniences of parenteral treatment; avoidance of the variablerates of absorption and metabolism inherent in oral treatment;increasing the continuity of drug administration by permitting deliveryof agents with short biological half-lives; and elimination ofgastrointestinal irritation resulting from exposing the gastrointestinaltract to pharmaceutical actives, preservatives, tableting agents, andthe like. Most importantly, topical delivery possesses the potential foreffectively treating conditions which are local in nature (or whichexhibit local manifestations), systemically as well as locally with thesame treatment regimen. Thus, effective compositions to deliverpharmaceutical agents are highly sought after

Although various compositions have been suggested for the precutaneousdelivery of certain pharmaceutically active agents, a need exists forachieving enhanced delivery of cosmetic and pharmaceutical agents to theskin for local treatment of skin conditions and diseases. In particular,the composition should be easy to apply topically in a quantitativeamount, to allow the active agent to rapidly permeate the skin to getwhere the agent is needed, to have a pleasant odor and appearance, andto not require cleansing to remove the agent.

This combination of these desired characteristics is difficult toachieve.

SUMMARY

The present disclosure relates to a composition for the local deliveryof at least one cosmetic or pharmaceutical agent or both. Thecomposition comprises at least two biocompatible organic solvents, apolar lipid, at least one surfactant, water, urea and a thickener. Theorganic solvents comprise an ester and a dihydric and/or polyhydricalcohol. The composition comprises about 2 to about 30% by weight of theester and about 2 to about 20% by weight of the dihydric and/orpolyhydric alcohol.

The present disclosure also relates to a method of delivering an activeagent into and through the epidermis tissue of a human or animalcomprising topically applying to the skin of the human or animal acomposition comprising a cosmetic and/or pharmaceutically active agentand the composition disclosed above.

Another aspect of the present disclosure relates to a compositioncomprising the above disclosed delivery composition and a cosmeticand/or pharmaceutically active agent. The pH of the compositioncontaining the active agent is typically about 5.5 to about 7.5.

A still further aspect of the present invention relates to a method formaking a composition suitable for the cutaneous delivery of a cosmeticand/or pharmaceutically active agent which comprises:

-   -   a. Dissolving a polar lipid at least in two biocompatible        organic solvents comprising at least one ester and at lease one        dihydric or polyhydric alcohol;    -   b. Adding one or more surfactants to the composition of step        (a);    -   c. Dissolving a cosmetic pharmaceutical and/or active compound        in the solvent-polar lipid, surfactant mixture of step (b);    -   d. Adding a urea and at least one thickener to water;    -   e. Combining the compositions from c and d and adjusting the pH        to about 5.5 to about 7.5, if necessary.

The present disclosure further relates to a composition prepared by theabove disclosed method.

Other objections and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein it is shown and described only thepreferred embodiments, simply by way of illustration of the best modecontemplated of carrying out the disclosure. As will be realized, thedisclosure is capable of other and different embodiments, and itsseveral details are capable of modifications in various obviousrespects, without departing from the disclosure. Accordingly, thedescription is to be regarded as illustrative in nature and not asrestrictive.

BEST AND VARIOUS MODES

By “topical administration”, as used herein, is meant directly laying orspreading upon epidermal tissue, especially outer skin or membrane,including the skin or membrane of the oral, rectal, or vaginal cavities.

By “safe and effective amount”, as used herein, is meant a sufficientamount of the composition to provide the desired local therapeuticactivity and performance at a reasonable benefit/risk ratio attendantany medical treatment. Within the scope of sound medical judgment, theamount of active agent used will vary with the particular conditionbeing treated, the severity of the condition, the duration of thetreatment, the specific active ingredient(s) employed, its or theirconcentration, the condition of the patient, concurrent therapies beingadministered, and like factors within the specific knowledge andexpertise of the patient or the attending physician.

By “toxicologically- or pharmacologically-acceptable”, as used herein,is meant the pharmaceutical actives, as well as other compatible drugs,medicaments or inert ingredients which the term describes are suitablefor use in contact with the tissues of human and lower animals withoutundue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio.

By the term “comprising”, as used herein, is meant that various othercompatible cosmetics, drugs and medicaments, as well as inertingredients, occlusive agents, and cosmetic vehicles, can be conjointlyemployed in the compositions and methods of this invention, as long asthe critical binary penetration enhancement vehicle and cosmetic orpharmaceutical active are used. The term “comprising” thus encompassesand includes the more restrictive terms “consisting of” and “consistingessentially of” which characterize the use of the essential ingredientsin the manner disclosed herein.

By “afflicted sites”, as used herein, is meant a localized area ofpathology, discomfort, infection, inflammation or lesion, and theimmediately surrounding area.

By “application sites”, as used herein, is meant a site suitable forapplication via a mechanical sustained release device or dressing, e.g.,behind the ear, on the arm, back, top of the foot, etc.

By “penetration-enhancing”, as used herein, is meant that the binarypenetration enhancing carriers of this disclosure provide markedtransepidermal or percutaneous delivery of an incorporated active, whencompared to other compositions at equal chemical potential. This latteraspect is important, since varying solubilities of cosmetics or drugs indifferent vehicles will necessarily affect their transport across skin.Thus, for example, if a drug is soluble in vehicle A to the extent of24%, and in vehicle B to the extent of 4%, were the compositions to becompared at equal percentage concentration, rather than equal chemicalpotential, the lower solubility carrier will show a misleading six-folddifference in transport over the more soluble vehicle. The simplest wayof assuring equal chemical potential for evaluating penetrationenhancement is to use saturated solutions or solutions of equalpercentage of saturation of pharmacological active in the variousvehicles.

By “substantially free”, as used herein, is meant that thepenetration-enhancing compositions of the present invention containsless than about 10%, preferably less than 3.5%, more preferably lessthan about 1%, and most preferably less than about 0.5%, of any specificcompound, or member of the group of compounds, described by this term.

As used herein, all percentages and ratios are by weight of the totalcomposition unless otherwise specified.

The terms “active”, “pharmaceutical active”, “pharmacological active”,“pharmaceutical agent”, “pharmacological agent”, “pharmaceutically-, orpharmacologically-active agent”, “chemical agent”, and “therapeuticagent”, are used interchangably herein.

The compositions of this disclosure contain a cosmetic agent and/orpharmaceutically-active agent capable of producing or possessing localactivity, in a binary vehicle or carrier. The vehicle on carriercomprises a polar lipid, such as lecithin or phosphotidylcholine, andtwo biocompatible organic solvents, one chosen from the group of estersand one chosen from the group of liquid dihydric and polyhydricalcohols, a surfactant, a preservative, water, and urea, at a pH ofbetween about 5.5 and 7.5 and preferably between 6.0 and 7.0. Thecompositions of this disclosure may additionally contain other optionalcomponents that reduce skin irritation, or enhance their cosmetic appealor acceptability, e.g, pigments, fragrances, perfumes, and the like.

Typical polar lipids employed are lecithin and phosphotidylcholine.Preferably, the lecithin or phosphatidylcholine is of a high quality,pharmaceutical grade. Appropriate lecithin and phosphatidylcholine maybeobtained as commercially available soya lecithin or soyaphosphatidylcholine. Preferably, soya lecithin is used in thecomposition of this invention.

The biocompatible organic ester solvents may be any non-toxic ester inwhich the polar lipid, the cosmetic or pharmaceutically active compoundand urea are soluble, and which assists as a solubilizing vehicle forcarrying cosmetic or pharmaceutically active compounds across the skinof a mammal.

Typically the esters are fatty mono esters having a structure,obtainable by replacing the active hydrogen of a fatty acid having 4 to22 carbon atoms and more typically having 8 to 18 carbon atoms by thealkyl group of a monohydric alcohol, particular example being 12 carbonatoms. The fatty acid can be saturated or unsaturated and more typicallyis saturated. The monohydric alcohol typically contains 2 to 8 carbonatoms and more typically 2 to 5 carbon atoms, a particular example being3 carbon atoms.

Acceptable esters for this purpose include, but are not limited toisopropyl esters. Preferably, the ester is isopropyl myristate orisopropyl palmitate, with isopropyl myristate being particularlypreferred.

The biocompatible organic dihydric and polyhydric alcohol solvents maybe any non-toxic di or polyalcohol in which the polar lipid, the activecompound and urea are soluble, and which assists as a solubilizingvehicle for carrying active compounds across the skin of a mammal.Acceptable dihydric and polyalcohols for this purpose include, but arenot limited to di- and tri-alcohol alkanes. Typically the alcoholscontain 3 to 8 carbon atoms and more typically 3 to 5 carbon atoms andare saturated alcohols. Preferably, the polyalcohol is propylene glycolor glycerol, with propylene glycol being particularly preferred.

The compositions of the present disclosure typically contain about 2 to30% by weight and more typically 4 to 10% by weight of the ester andabout 2 to about 20% by weight and more typically 2 to about 10% weightof the alcohol.

In preparing the composition of this disclosure, the polar lipid istypically dissolved in the organic ester solvent and di or polyalcoholsolvent at mass ratios from about 5:1:1 to about 1:5:5. Preferably, thepolar lipid and organic ester solvent and polyalcohol solvent are mixedin equal mass ratios. Thus, in one embodiment of the invention, soyalecithin, isopropyl myristate, and propylene glycol are mixed in equalmass ratios and mixed until the lecithin is evenly distributed. This isreferred to as the solvent-polar lipid mixture.

Depending on the nature of the cosmetic or pharmaceutically activecompound and the desired characteristics of the final formulation, asurfactant can be included in the formulation at a concentration ofbetween about 1-20% of the final composition mass. In the formulationincluding a polycationic active agent, it has been found, according tothis disclosure that non-ionic or cationic surfactants are preferred. Inthe case of other active ingredients, on the other hand, anionic,cationic or non-ionic surfactants are quite acceptable. Preferably, thesurfactant is one which is compatible with administration in vivowithout elicitation of undesirable side effects. One preferredsurfactant is docusate sodium and its more water soluble form, docusatesodium benzoate. Other appropriate ionic or non-ionic surfactants, suchas polysorbate 80, Tween 80 docisate calcium,tetradecyltrimethylammonium bromide, pentaoxyetylene glycol monododecylether, or triethanolamine laureth sulfate. Once the surfactant isthoroughly dispersed in the solvent-polar lipid mixture, the cosmetic orpharmaceutically active compound may be added and dissolved.

The dosage of the cosmetic or pharmaceutical agent will, of course, varydepending upon known factors, such as the cosmetic or pharmaceuticalagent characteristics of the particular agent; the age, health andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; and the effectdesired. A daily dosage of active ingredient can be expected to be about0.001 to 1000 milligrams (mg) per kilogram (kg) of body weight, with themore typical dose being 0.1 to about 30 mg/kg.

The active agent is typically present in amounts of about 0.001 to about30%, more typically about 0.001 to about 20%, and even more typicallyabout 0.5 to 12% by weight based upon the total of the delivery systemand active agent. For solid active ingredients, this is most easilyachieved by heating an aliquot of the surfactant-solvent-polar lipidmixture and adding, on a mass basis, an amount of active compound equalto about 0.01 to 30% of the mass of the surfactant-solvent-polar lipidand mixing until completely dissolved. Thus, for example, about 1-20grams of nifedipine in a powdered form is added to about 100 grams ofheated 1:0.5:0.5 soya lecithin:isopropyl myristate:propylene glycol andallowed to dissolve with stirring.

Same exemplary active agents include vasodilating agents such asglyceryl trinitrate and nifedipine; antimicrobial agents such asciclopirox, itraconazole, metronidazole, miconazole and terbinafine;inhibitors of cell growth or proliferation, such as 2-deoxy-D-glucose;inhibitors of polyamine transport; inhibitors of polyamine synthesis;antizyme inducers; decalcifying skin agents such as lactic acid;anti-inflammatory agents such as ibuprofen and ketoprofen; topicalanaesthetics such as lidocaine; steroidal anti-inflammatory compounds,such as cortisone; peptides, proteins, or hormones, such as plateletfactor 4; substance P antagonists such as capsaicin; muscle relaxantssuch as cyclobenzaprine; anti-inflammatory analgesics such as diclofenacsodium and phosphodiesterase inhibitors such as sudenifil.

In the event a volatile active agent or proteinaceous active agent isused, adding the active agent to a relatively warm solution ofsurfactant-solvent polar lipid mixture is not usually desired as thismight decrease the amount of active agent in the final formulation.

By way of specific examples, in the case of the active nitroglycerin,the active is available in the form of a 10% concentration in propyleneglycol, which can be added directly to the polarlipid-solvent-surfactant mixture.

The amount of a vasodilator for the treatment of peripheral arterialdiseases, including Raynaud's Disease, diabetic paresthesia, and nightleg cramps is typically about 0.2 to about 1.8% of the composition.

The amount of antimicrobial agent for the treatment of infectiousdiseases of the skin, including onychomycois, athlete's foot, rosacea,and vaginomycosis is typically about 0.5 to about 12% by weight.

The amount of an inhibitor of cell growth or proliferation for treatmentof actinic keratosis is about 0.001 to about 10% of weight.

The amount of an inhibitor of polyamine transport is typically about0.001 to about 5% by weight. The amount of an inhibitor of polyaminesynthesis for the treatment of an automimmune disease, includingcutaneous lupus erythrematosus, urticaria, psoriasis, and atopicdermatosis is typically about 0.001 to about 5% by weight.

The amount of a decalcifying skin agent, such as lactic acid, for thetreatment of dry skin conditions, including xerosis, scleroderma, andichthyosis is typically about 0.5 to about 10% by weight.

It is further understood that two or more different types of activeagents can be employed in order to treat more than one condition at thesame time. For instance, two or more active agents can be used to treatinflammatory, autoimmune, infectious and/or dry skin conditionssimultaneously.

After addition of the cosmetic or pharmaceutically active compound, anamount of urea, preferably as a thickened aqueous solution, can be addedto the surfactant-solvent-polar lipid mixture. The urea is typicallyadded so that the urea concentration about 1% to about 15% and moretypically about 5% and 10% by mass of the final composition mass.

The thickener is selected from common National Formulary thickeningagents including, but not limited to appropriate polymer weights ofpolyethylene glycol, polyvinylpyrrolidone, carbomer and methylcellulose.The amount of thickener is typically about 0.05 to about 5% by weight.

Thus in a specific example, about 5 grams of a 10% aqueous solution ofurea, containing 0.7% Carbomer 934, is added to about 100 grams of thesurfactant-solvent-polar lipid mixture with dissolved pharmaceuticallyactive compound. In some instances, the pharmaceutically active agentwill more readily dissolve if added after addition of the aqueous ureasolution, and in other instances before the addition of aqueous ureasolution. In any event, this is a choice readily made by those skilledin the art, once aware of the present disclosure, depending on theparticular formulation being prepared and the solubility characteristicsof the particular cosmetic or pharmaceutically active compound beingsolubilized. If the active agent is a protein, it will be necessary totest the retention of biological activity of the protein upon exposureto the particular urea concentration used in this formulation as thechaotropic properties of urea are known to denature some proteins. Sucha determination is easily conducted by one of ordinary skill in the art.

Upon formulation of the above described composition with the cosmetic orpharmaceutically active agent, the pH is adjusted to typical pH of about5.5 to about 7.5 and more typically to a 6.0 to 7.0. This can beaccomplished, for example, by addition of aqueous sodium hydroxide, asthe compositions initially tend to have an acid pH. However, if thepharmaceutically active agent tends to produce very alkaline solutions,addition of acid to reduce the pH would be desirable. This can beaccomplished by addition of citric acid or a biological buffer such assodium carbonate or potassium phosphate. With the composition in a pHrange of about 5.5 to 7.5, the formulation thickens and forms a creamygel for topical administration.

In one embodiment of the invention, the composition is formulated with avasodilating agent, such as glyceryl trinitrate. Such formulation israpidly absorbed through the skin and provides local vasodilation,increases in blood flow, and restoration of normal temperature to anextremity with low blood flow. In another embodiment of the invention,the composition is formulated with an anti-infective agent. Suchformulation is rapidly absorbed through the skin to provide localdelivery to kill invading microorganisms such as fungi or bacteria.

By routine experimentation, using the recited elements of thiscomposition, those skilled in the art, once aware of the presentdisclosure, will be able to make specific gels of essentially any activeingredient or combination thereof for a wide variety of typicalapplications. In addition, it is understood that the compositions cancontain auxiliary agents including those conventionally known and/orused in this art such as, but not limited to, preservatives andfragrances.

For ease of preparation, it is convenient to prepare a first gelcomposition, referred to herein as “MQX-GEL”, which can be used to addto other components in the formulation of a final composition fortopical administration. There are several possible formulations of theMQX-GEL. For example, a MQX-GEL may be prepared by mixing lecithinorganogel (L.O.), as a 1:1:1 (m/m/m) mixture of lecithin, isopropylmyristate and propylene glycol, with LID oil (a 1:1 [m/m] mixture ofL.O. and docusate sodium), dissolving additional surfactant and/ordocusate sodium powder into this mixture, and then adding thickenedaqueous urea.

In one embodiment of the MQX-GEL formulation, the final concentrationsare: L.O.=30%; docusate sodium=9%; urea=5%; thickener=1%; and water=55%.These ratios may easily be varied such that the final amounts of eachcomponent are as follows: L.O.=15-50%; docusate sodium and/or anothersurfactant=3-15%; urea=1-15%; thickener=0.5-5%; and water=40-65%. Thesolubilized active ingredients may then be added to MQX-GEL. Excipientswhich may be useful in solubilizing the active ingredient include L.O.,propylene glycol, isopropyl myristate, peppermint oil, glycerin, and/orpolyethylene glycol. A homogenous mixture is then made by carefullyblending the various components.

Once the formulations described above have been prepared, use of theformulations is a simple matter of applying the formulation to affectedareas where cutaneous delivery of the pharmaceutically active agent isdesired. Thus, in the case of Raynaud's phenomenon, formulationscontaining glyceryl trinitrate are rubbed over the affected area such asthe fingers of the hands. Treatment is repeated as symptoms reappear. Inuse of formulations prepared according to this invention, normal bloodflow in the fingers of the Raynaud's patient has been restored withinfive minutes of application.

In another aspect of this invention, an anti-fungal anti-microbialcompound is formulated for delivery to toe nails infected with fungus.In nine-month treatments, doctors and patients across the country haveconfirmed almost complete reduction in fungal infection. This is incontrast to results observed with current commercial topicalformulations with this same active ingredient that provide very modestreduction in fungal infection in the same time frame.

In another aspect of this invention, a composition comprising anantibacterial agent is prepared, for example, by inclusion of bacitracinor another appropriate antibiotic. This allows for penetration of theantibacterial agent to sites of infection induced by puncture wounds.

In general, compositions of this invention are provided at aconcentration of between about 0.001% to 30% by weight of activecompound. In addition, compositions comprising more than one activeingredient are within the scope of this invention and could beadministered to a recipient in need of more than a single activetreatment at one localized spot. Thus, for example, a compositioncomprising a vasodilating agent and an antifungal would both providerelief from fungal infection and will facilitate long-term relief byrestoring blood flow and the flow of nutrients to the affected area.

It is contemplated that the compositions of this invention are appliedtopically as frequently as required as long as local reactions ortoxicity due to the active ingredient do not become a problem. Thus, forexample, a more rigorously monitored regimen of application may berequired when an anti-neoplastic compound is being administered thanwhen a readily metabolized non-toxic compound such as ketoprofen isadministered. In the latter case, it would be acceptable for a person inneed of such treatment to topically apply the composition as frequentlyas needed to achieve relief from local pain or inflammation.

While the foregoing description generally describes how to make and usethe compositions and formulations of this invention, the followingexamples are provided to more specifically point out how to practice theinvention. However, it should be clearly understood that the scope ofthis invention, as defined by the claims appended hereto, is not to belimited to the specifics of the following examples. Further, it shouldbe understood that, in the specific compositions described and claimed,the percentages of active and other ingredients could be within at leasta 10% different amount while still achieving an objective equivalent tothe specifically disclosed compositions.

The following non-limiting examples are presented to further illustratethe present disclosure:

EXAMPLE 1 Preparation of MQX-GEL

500 gm LID Oil* 50 gm Lecithin organogel** (L.O.) 100 gm Docusate sodiumpowder 50 gm Urea 50 gm Thickener 5 gm Distilled water 245 ml *LID oilis a 1:1 mixture of lecithin organogel:docusate sodium on a mass basis.**L.O. is a 1:1:1 mixture of lecithin, isopropyl myristate and propyleneglycol.1. The LID was added to L.O. and heated.

-   2. Docusate sodium powder was added, and the mixture was stirred    until smooth.-   3. Thickener and urea were completely dissolved in water, heated,    and added to step 2 with stirring.-   4. pH was adjusted to between 6.5 to 6.9.    MQX-GEL may just as easily be prepared as follows:

1000 gm L.O. 250 gm Docusate sodium benzoate powder 150 gm Urea 100 gmThickener 10 gm Distilled water 490 ml

The L.O. was heated and the docusate sodium benzoate powder was stirredinto the heated L.O. until a smooth solution is prepared. The water washeated and the thickener and urea were dissolved into the water, and thethickened urea solution was then thoroughly mixed with the docusatesodium containing solution of L.O. The result was a consistent,transparent, amber colored gel with a pH of about 6.0.

A further method of making MQX-GEL is as follows:

1000 gm L.O. 100 gm LID 300 gm Urea 100 gm Thickener  10 gm Distilledwater 490 gm

The LID and L.O. were mixed well and a heated solution of water, thethickener and the urea was prepared and added to the LID-L.O. solution.The result was a consistent, transparent, amber colored gel with a pH ofabout 6.0.

EXAMPLE 2 Preparation of 1.2% Glyceryl Trinitrate Gel

500 gm Glyceryl Trinitrate  6.0 gm (as 10% active in propylene glycol or54.0 gm of propylene glycol) Lecithin organogel (L.O.) 90.0 gm DocusateSodium 22.6 gm Urea 25.1 gm Carbomer 934  3.5 gm Methylcellulose  4.4 gmWater, distilled 294.4 gm 

-   1. Docusate sodium is added to L.O. and stirred to obtain a clear    solution.-   2. Glyceryl trinitrate (as 10% active in propylene glycol) is added    to solution of step 1.-   3. Urea is added to distilled water, with heating and stirring to    obtain a uniform solution.-   4. Carbomer 934 and Methylcellulose are added to thicken the    urea-water of step 3.-   5. The lecithin organogel with the active from step 2 is combined    with the thickened aqueous urea from step 4 to form a uniform    mixture.-   6. The pH is adjusted to 6.5 with dilute aqueous NaOH to form an    elegant thick gel.

EXAMPLE 3 Preparation of 0.5% Glyceryl Trinitrate Gel

500 gm Glyceryl Trinitrate 2.5 gm (as 10% active in propylene glycol or22.5 gm of propylene glycol) Lecithin organogel (L.O.) 125.0 gm Docusate Sodium 22.6 gm  Urea 25.1 gm  Carbomer 934 3.5 gmMethylcellulose 4.4 gm Water, distilled 294.4 gm 

The same method of combining the ingredients is used as described inexample 2.

MQX-GEL can also be prepared with other ratios of the three constituentsof the lecithin organogel. In the following example, the ratio oflecithin organogel (L.O. #2), is a 1:0.9:0.1 (m/m/m) mixture oflecithin, isopropyl myristate and propylene glycol, with LID oil (a 1:1[m/m] mixture of L.O.#2 and docusate sodium), dissolving additionalsurfactant and/or docusate sodium powder into this mixture, and thenadding thickened aqueous urea.

In this embodiment of the MQX-GEL formulation, the final concentrationsare: L.O.#2=25%; docusate sodium=10%; urea=10%; thickener=1%; andwater=54%. These ratios also may easily be varied such that the finalamounts of each component are as follows: L.O.#2=15-50%; docusate sodiumand/or another surfactant=3-15%; urea=1-15%; thickener=0.5-5%; andwater=40-65%. The solubilized active ingredients may then be added toMQX-GEL. Excipients which may be useful in solubilizing the activeingredient include L.O.#2, propylene glycol, isopropyl myristate,peppermint oil, glycerin, and/or polyethylene glycol. A homogenousmixture is then made by carefully blending the various components.

EXAMPLE 4 Preparation of Another 1.2% Glyceryl Trinitrate Gel

500 gm Glyceryl Trinitrate 6.0 gm (as 10% active in propylene glycol or54.0 gm of propylene glycol) L.O. #2 115.0 gm  Docusate Sodium 45.0 gm Urea 45.0 gm  Carbomer 934 3.5 gm Methylcellulose 4.4 gm Water,distilled 227.1 gm The same method of combining the ingredients is used as in example 2.

EXAMPLE 5 Preparation of 0.5% Glyceryl Trinitrate Gel

500 gm Glyceryl Trinitrate 2.5 gm (as 10% active in propylene glycol or22.5 gm of propylene glycol) L.O.#2 150.0 gm  Docusate Sodium 45.0 gm Urea 45.0 gm  Carbomer 934 3.5 gm Methylcellulose 4.4 gm Water,distilled 227.1 gm The same preparation method was used in this example as in the previousone.

EXAMPLE 6 Preparation of 8.0% Ciclopirox Gel

500 gm Ciclopirox 40.0 gm L.O.#2 128.9 gm  Docusate Sodium 45.0 gm Urea45.0 gm Carbomer 934  2.6 gm Methylcellulose  1.5 gm Water, distilled237.0 gm 

-   1. Docusate sodium is added to L.O.#2 and stirred to obtain a clear    solution.-   2. Ciclopirox is added to solution of step 1.-   3. Urea is added to distilled water, with heating and stirring to    obtain a uniform solution.-   4. Carbomer 934 and Methylcellulose are added to thicken the    urea-water of step 3.-   5. The lecithin organogel with the active from step 2 is combined    with the thickened aqueous urea from step 4 to form a uniform    mixture.-   6. The pH is adjusted to 6.5 with dilute aqueous NaOH to form an    elegant thick gel.

EXAMPLE 7 Preparation of 15.0% Lactic Acid Gel

500 gm Lactic Acid 75.0 gm L.O.#2 118.9 gm  Docusate Sodium 30.0 gm Urea45.0 gm Carbomer 934  2.6 gm Methylcellulose  1.5 gm Water, distilled232.0 gm The same method of preparation is used as in example 6.

EXAMPLE 8 Preparation of 8% Ciclopirox, 1% Glyceryl Trinitrate Gel

500 gm Glyceryl Trinitrate  5.0 gm (as 10% active in propylene glycol or45.0 gm of propylene glycol) Ciclopirox 40.0 gm L.O. #2 115.0 gm Docusate Sodium 35.0 gm Urea 35.0 gm Carbomer 934  2.8 gmMethylcellulose  1.7 gm Water, distilled 220.5 gm 

-   1. Docusate sodium is added to L.O.#2 and stirred to obtain a clear    solution.-   2. Ciclopirox and Glyceryl trinitrate, as 10% solution in propylene    glycol, is added to solution of step 1.-   3. Urea is added to distilled water, with heating and stirring to    obtain a uniform solution.-   4. Carbomer 934 and Methylcellulose are added to thicken the    urea-water of step 3.-   5. The lecithin organogel with the actives from step 2 is combined    with the thickened aqueous urea from step 4 to form a uniform    mixture.-   6. The pH is adjusted to 6.5 with dilute aqueous NaOH to form an    elegant thick gel.

EXAMPLE 9 Preparation of 10% Ibuprofen, 0.5% Glyceryl Trinitrate Gel

500 gm Glyceryl Trinitrate 2.5 gm (as 10% active in propylene glycol or22.5 gm of propyleneglycol) Ibuprofen 50.0 gm L.O. #2 135.0 gm DocusateSodium 15.0 gm Urea 35.0 gm Carbomer 934 2.8 gm Methylcellulose 1.7 gmWater, distilled 220.5 gm

-   1. Docusate sodium and ibuprofen are added to L.O.#2 and stirred to    obtain a clear solution.-   2. Glyceryl trinitrate, as 10% solution in propylene glycol, is    added to solution of step 1.-   3. Urea is added to distilled water, with heating and stirring to    obtain a uniform solution.-   4. Carbomer 934 and Methylcellulose are added to thicken the    urea-water of step 3.-   5. The lecithin organogel with the actives from step 2 is combined    with the thickened aqueous urea from step 4 to form a uniform    mixture.-   6. The pH is adjusted to 6.5 with dilute aqueous NaOH to form an    elegant thick gel.

EXAMPLE 10 Preparation of 5.0% 2-Deoxy-D-Glucose Gel

500 gm 2-Deoxy-D-Glucose 25.0 gm L.O. #2 128.9 gm Docusate Sodium 45.0gm Urea 45.0 gm Carbomer 934 2.6 gm Methylcellulose 1.5 gm Water,distilled 252.0 gm

-   1. Docusate sodium is added to L.O.#2 and stirred to obtain a clear    solution.-   2. 2-Deoxy-D-Glucose is added to solution of step 1.-   3. Urea is added to distilled water, with heating and stirring to    obtain a uniform solution.-   4. Carbomer 934 and Methylcellulose are added to thicken the    urea-water of step 3.-   5. The lecithin organogel with the active from step 2 is combined    with the thickened aqueous urea from step 4 to form a uniform    mixture.-   6. The pH is adjusted to 6.5 with dilute aqueous NaOH to form an    elegant thick gel.

The foregoing description illustrates and describes the presentdisclosure. Additionally, the disclosure shows and describes only thepreferred embodiments of the disclosure, but, as mentioned above, it isto be understood that it is capable of changes or modifications withinthe scope of the concept as expressed herein, commensurate with theabove teachings and/or the skill or knowledge of the relevant art. Theembodiments described hereinabove are further intended to explain bestmodes known of practicing the invention and to enable others skilled inthe art to utilize the disclosure in such, or other, embodiments andwith the various modifications required by the particular applicationsor uses disclosed herein. Accordingly, the description is not intendedto limit the invention to the form disclosed herein. Also, it isintended that the appended claims be construed to include alternativeembodiments.

All publications, patents and patent applications cited in thisspecification are herein incorporated by reference, and for any and allpurposes, as if each individual publication, patent or patentapplication were specifically and individually indicates to beincorporated by reference. In the case of inconsistencies, the presentdisclosure will prevail.

1. A composition suitable for the delivery of at least one cosmeticagent or pharmaceutical agent or both through the skin of a mammal,which comprises two biocompatible organic solvents, 6 to 30% by weightof lecithin, 0.5 to 15% by weight of at least one or more surfactant,wherein said surfactant comprises a docusate, 40 to 65% by weight water,1 to 15% by weight of urea and 0.05 to 5% by weight of a thickener;wherein the organic solvents comprise isopropyl myristate and propyleneglycol; and wherein the composition comprises 2 to 30% of the isopropylmyristate and 2 to 20% of the propylene glycol.
 2. The composition ofclaim 1, wherein the at least one surfactant is selected from the groupconsisting of docusate sodium, docusate sodium benzoate, and docusatecalcium.
 3. The composition according to claim 1, wherein the thickeneris selected from the group of polyethylene glycol, methyl cellulose, andcarbomer.
 4. The composition of claim 1, wherein the amount of thelecithin is 10 to 30% by weight.
 5. The composition of claim 1, furthercomprising at least one of a cosmetic agent or pharmaceutical agent orboth.
 6. The composition of claim 5, wherein the amount of the cosmeticagent or pharmaceutical agent or both is 0.001 to 30% by weight.
 7. Thecomposition of claim 5, having a pH of about 5.5 to about 7.5.
 8. Thecomposition of claim 7, wherein the pH is about 6 to about
 7. 9. Thecomposition of claim 1, further comprising at least 0.2-1.8% of avasodilating agent.
 10. The composition of claim 9, wherein thevasodilating agent is glyceryl trinitrate.
 11. The composition,according to claim 1, further comprising 1 to 12% of an antimicrobialagent.
 12. The composition of claim 11, wherein the antimicrobial agentis selected from the group consisting of ciclopirox, itraconazole,metronidazole, and terbinafine.
 13. The composition of claim 1, furthercomprising 0.001-10.0% of an inhibitor of cell growth or proliferation.14. The composition of claim 13, wherein said inhibitor is2-deoxy-D-glucose.
 15. The composition, according to claim 1, furthercomprising 0.001-5.0% of an inhibitor of polyamine transport or0.005-5.0% of an inhibitor of polyamine synthesis.
 16. The composition,according to claim 1, further comprising 0.001-5.0% of an antizymeinducer.
 17. The composition, according to claim 1, further comprising0.5-10% of a decalcifying skin agent.
 18. The composition of claim 17,wherein the decalcifying skin agent is lactic acid.
 19. The composition,according to claim 1, further comprising at least two activeingredients.
 20. A method of delivering an active agent into and throughthe epidermis tissue of a human or animal which comprises topicallyapplying to the skin of the human or animal a composition according toclaim
 5. 21. A method of making a composition suitable for cutaneousdelivery of a pharmaceutically active substance which comprises: a.dissolving 6 to 30% by weight of lecithin, at least in two biocompatibleorganic solvents comprising isopropyl myristate and propylene glycol; b.adding 0.5 to 15% of one or more surfactants to the composition of step(a), wherein the one or more surfactants comprise a docusate; c.dissolving a pharmaceutically active compound in the solvent-lecithin,surfactant mixture of step (b); d. adding 1 to 15% by weight of urea and0.05 to 5% by weight of a thickener to water; and e. combining thecomposition from c and d and optionally adjusting the pH to about 5.5 toabout 7.5; wherein the amount of water is 40 to 65% by weight, theamount of isopropyl myristate is 2 to 30% by weight, and the amount ofpropylene glycol is 2 to 20% by weight.
 22. A composition suitable forcutaneous delivery of a pharmaceutically active substance prepared by amethod which comprises: a. dissolving 6 to 30% by weight of lecithin, atleast in two biocompatible organic solvents comprising isopropylmyristate and propylene glycol; b. adding 0.5 to 15% by weight of one ormore surfactants to the composition of step (a); c. dissolving apharmaceutically active compound in the solvent-lecithin, surfactantmixture of step (b); d. adding 1 to 15% by weight of urea and 0.05 to 5%by weight of a thickener to water; and e. combining the composition fromc and d and optionally adjusting the pH to about 5.5 to about 7.5;wherein the one or more surfactants comprise a docusate, the amount ofwater is 40 to 65% by weight, the amount of the isopropyl myristate is 2to 30%, the amount of the propylene glycol, is 2 to
 20. 23. Thecomposition of claim 1, wherein at least one surfactant is selected fromthe group consisting of docusate sodium, docusate sodium benzoate, anddocusate calcium, the thickener is selected from the group ofpolyethylene glycol, methyl cellulose, and carbomer.